Summary GABAergic interneurons (INs) are a diverse group of neurons with critical roles in signal processing in the cerebral cortex. Moreover, malfunction of these neurons has been implicated in a number of diseases ranging from epilepsy to schizophrenia, anxiety disorders and autism. This project is focused on the GABAergic INs that express the neuropeptide somatostatin (SST). These cells represent the second largest family of INs in the neocortex. SST INs make synapses on the dendrites of pyramidal cells (PCs) and other interneurons and have been shown to be important for dendritic integration, as well as non-linear dendritic operations, Ca2+ signaling, and plasticity. SST INs were recently suggested, based on the analysis of their patterns of in vivo activity in multiple types of sensory cortices, to be involved in a disinhibitory canonical circuit that is thought to be important in brain state-dependent control of cortical function. However, these studies have been limited to superficial cortical layers. Using a new method for the in vivo recording and labeling of genetically-tagged neurons throughout the brain we recorded for the first time from SST IN throughout the whole cortical column and discovered an unappreciated diversity of SST INs in L5/6 of somatosensory cortex. SST IN subtypes differed in the laminar distribution of their axon and had distinct patterns of in vivo activity. Taking advantage of our expanded understanding of SST IN diversity and the availability of novel genetic tools that allow the identification and manipulation of SST IN subtypes with increased specificity, the goal of this project is to test the hypothesis that SST IN subtypes differentially control the activity of specific PC dendritic branches during behavior. We will study the connectivity of L5/6 SST IN subtypes to different types of L5 PCs and determine the subcellular localization of IN synapses on the L5 PC dendrite (Aim 1). In Aim 2 electrophysiological recording, Ca2+ imaging and optogenetic manipulations will be used to investigate the function of distinct SST In subtypes on active touch responses in pyramidal cells and their cross-modal modulation by sound. Aim 3 will develop an experimentally-based model of the selective gating of information in PC dendrites mediated by SST IN subtypes. These studies will advance our understanding of SST IN function and the mechanisms of top down modulation of sensory processing.